Role of factor XIII in ischemic stroke: a key molecule promoting thrombus stabilization and resistance to lysis.

BACKGROUND:Active coagulation factor XIII (FXIIIa) catalysing crosslinking of fibrin and other hemostatic factors, plays a key role in clot stability and lysis. OBJECTIVE:To evaluate the effect of FXIII inhibition in a mouse model of ischemic stroke (IS), and the role of FXIIIa in clot formation and lysis in IS patients. METHODS:FeCl3 IS murine model was performed before and after administration of a FXIIIa inhibitor (FXIIIinh). Thromboelastometry in human and mice blood was used to evaluate thrombus stiffness and lysis with FXIIIinh. FXIIIa-dependent fibrin crosslinking and lysis with fibrinolytic drugs (tPA and TNK) were studied on fibrin plates, and on thrombi and clotted plasma of IS patients. Finally, circulating and thrombus FXIIIa were measured in 85 IS patients. RESULTS:FXIIIinh administration before stroke-induction reduced infarct size, α2AP crosslinking, and local microthrombosis, improving motor coordination and fibrinolysis, without intracranial bleeds (24h). Interestingly, FXIII blockade post-stroke also reduced brain damage and neurological deficit. Thromboelastomety in human/mice blood with FXIIIinh, showed delayed clot formation, reduced clot firmness, and shortened tPA-lysis time. FXIIIa fibrin cross-linking increased fibrin density and lysis resistance that further raised after α2AP addition. FXIIIinh enhanced ex-vivo lysis in stroke thrombi and fibrin plates. In IS patients, thrombus FXIII and α2AP were associated with inflammatory and hemostatic components, and plasma FXIIIa correlated with thrombus α2AP and fibrin. CONCLUSIONS:Our results suggest a key role of FXIIIa in thrombus stabilization, α2AP crosslinking, and lysis resistance, with a protective effect of FXIIIinh in an IS experimental model.